This book originates from a symposium held at the London Hospital Medical College under the auspices of Applied Chromatography Systems Ltd. to discuss the place of HPLC in the endocrinology field. Many of the authors of the present book were speakers at this symposium. It seemed to us that many endocrinolo gists did not at that time fully appreciate the value of HPLC, and this book was designed to publicise the potential value of this technique. A survey of methods used in the steroid field Cp 185) confirmed the view that HPLC is not being used as widely, particularly in research described in clinical journals, as might be expected. We hope that this book will illustrate, albeit in a few selected areas of endocrinology, just how versatile and powerful a technique HPLC is, and en courage those who have not yet experienced it to have a go. The beginner does not need to buy expensive instrumentation - all that is required is a pump, injector, column and detector - the rest can come later! All the authors have practical experience in the use of HPLC in the particular area they discuss. All readers who discover apparent errors or who feel that the treatment of a topic of interest can be improved upon are encouraged to contact the editors. All criti cism, especially if constructive, is welcomed. We are still learning, and other peoples' experience is always valuable.

The field of human artificial reproductive technology (ART) is continually advancing and has witnessed significant changes since the inception of Louise Brown in 1978. Though Louise Brown herself was conceived after the trans fer of a blastocyst, there remain significant confusion and debate regarding the stage at which the human embryo conceived in the laboratory should be replaced in the mother. Developments in culture media formulations, leading to the introduction of sequential media, have brought the role of the blasto cyst in human ART back into the spotlight. It was due to this resurgence of interest in the niche of extended culture in human infertility treatment that the symposium on "ART and the Human Blastocyst" was held. of this meeting within this volume bring to the forefront The proceedings the main issues raised with the transfer of embryos at the blastocyst stage. It is evident from the chapters that follow that ART needs to be perceived as a continuum of procedures, each one dependent on the preceding one, and all equally as important as each other. That is to say, the development of a com petent embryo is ultimately dependent on the quality of the gametes from which it was derived. With regard to the oocyte, this then places the emphasis on the physician to use a stimulation protocol that both produces quality oocytes and does not impair endometrial function. Maintenance of gamete and embryo quality is the laboratory's role.

The eleventh monograph and meeting of the Foundation on "Hormon al Control of the Hypothalamo-Pituitary-Gonadal Axis" was held in October 1983 at the Weizmann Institute of Science. This monograph honors the memory of Professor Hans R. Lindner, a productive and innovative scientist greatly respected and admired by his col leagues. When addressing the opening session I remarked that my impres sion of the Weizmann Institute was one or two large buildings hous ing the various departments. This was my first visit to Israel and I was overwhelmed by the beautiful semi-tropical gardens of the in stitute, in a setting of shrubs and trees, orange groves and flow ers. Sited among this seventy-five acres are over fifty buildings and residential areas for the staff and visiting scientists. I saw pictures of this area when Dr. Chaim Weizmann founded in 1934, the Daniel Sieff Research Institute, the forerunner of the Weizmann In stitute. The site was sand dunes without a blade of grass. That the desert shall bloom is illustrative of the progress made in Is rael. The topics of the monograph are grouped into twelve sections.

Changes in the allocation of healthcare resources have raised issues related to the efficacy and outcomes of medical therapy and how such factors may be measured. The questions associated with the quality of life and functional capability of patients with chronic health conditions have been of special interest. Endocrine disorders have the potential for disrupting the general health and well-being of affected individuals and their families; thus they warrant serious attention. This symposium was convened in November 1997 at Palm Beach Gardens, Florida, to bring together medical, behavioral, and social scientists. The meeting fostered the presentation and discussion of the most current clinical research on the effects of various therapies on a wide range of endocrine disorders from diabetes to adrenal insufficiency and growth hormone deficiency. The participants, all noted national and international experts in their fields, focused their attention on both the biomedical value and effectiveness of treatment, as well as on the impact such treatments have on psychological states such as mood and cognition. Many presentations specifically emphasized the quality of life (QOL) indicators that now regu larly appear in many research protocols and reports. The pioneering work of two clinical researchers was a major highlight of the meeting and an Award of Recognition was presented to Robert Blizzard, M. D. , and John Money, Ph. D. , for their innovative and insightful work in pediatric endocrinology and psychosexual development.

As I reflect on the evolution of this book, I am struck by the differences be tween my early conceptions and the final product. When I was first ap proached by Springer-Verlag regarding a monograph on my interests in the area of fetal lung development, I imagined that it would be relatively easy to summarize my contributions, plus the work of other investigators as needed for proper perspective. This rather naive idea was abandoned as I prepared my initial outlines for the monograph. I quickly realized that con tributions from my laboratory are not sufficient for telling the story of "hormones and lung maturation." The result of this decision is a longer and more heavily-referenced book than I originally envisioned. Although I have attempted to discuss in considerable detail most aspects of hormones and the fetal lung, I know with certainty that I have not in cluded all relevant references in each area. In most of these instances this reflects my impatience or lack of diligence, and I offer my apologies to those investigators whose work has been so omitted. In some situations published work has not been cited in a deliberate decision to limit the breadth of discussion or, rarely, due to my judgment of major shortcom ings in experimental design or execution."

The tridecapeptide neurotensin (NT) was first identified in bovine hypothalamic extracts and characterized by Carraway and Leeman (1973,1975,1976) and has subsequently been found in all classes of vertebrates (Carraway and Leeman 1976; Kitabgi et al. 1976; Kataoka et al. 1979; Langer et al. 1979; Reinecke et al. 1980a; Cooper et al. 1981; Grant et al. 1982; Carraway et al. 1982; Eldred and Karten 1983), many invertebrates (Reinecke et al. 1980 b; Grimmelikhuijzen et al. 1981; Price et al. 1982), and certain bacteria (Bhatnagar and Carraway 1981). It is distributed throughout the mammalian central nervous system (CNS) (Uhl and Snyder 1977 a, b), gastrointestinal tract (Sundler et al. 1977; Schultzberg et al. 1980), cerebrospinal fluid (CSF), adrenals, pancreas, and plasma (Fernstrom et al. 1980). When administered systemically, the peptide has a variety of effects such as hypotension, hyperglycemia, decreased gastric acid secretion, decreased gut motility, and altered secretion of anterior pituitary hormones (Leeman and Carraway 1982). NT apparently does not cross the blood-brain barrier in appre- ciable quantities; however, when administered directly into the CNS, it produces a number of physiological and behavioral effects. A burgeoning body of evidence supports the role of NT as a neurotransmitter or neuromodulator. Thus far, het- erogeneous CNS distribution, release of NT upon neuronal depolarization, satu- rable and specific binding of NT to receptors, and degradation by peptidases have all been demonstrated.

Upon wresting the control of the earth from the Titans, Zeus assigned the task of creating living creatures to two Titan brothers who had sided with him in the epic battle just concluded. Because Epimetheus, who had been endowed only with hindsight, had the first hand in this creation, all the good attributes were exhaus ted by the time the lion, the elephant and other animals were created. When the time came for the creation of man, there were precious few materials left to work with. Not surprisingly, man was made weak and naked. Prometheus took pity on this miscreation and gave man the use of fire. For this foresight, Zeus meted out horrible punishment, binding Prometheus to a rocky pillar in the Caucasas Moun tains and letting a vulture consume his liver daily. It seems to me that the ancient Greeks in their unfathomable wisdom under stood the essence of the evolutionary process very well. Had Escherichia coli of 200 million years or so ago been endowed with the foresight to anticipate the eventual emergence of and subsequent dominance by mammals of this Earth, they would no doubt have equipped themselves, in anticipation of the coming cer tainty, with the lac operon to deal with lactose in the suckling mammalian infant's gut. Had they been able to do so, the actual emergance of mammals would have exerted no selective pressure upon existing E. COLI."

Endocrinologic investigations during pregnancy have focused in the last decades on placental hormones, the maternal endocrine system and maternal fetal interactions. Less is known about the fetus itself and the interaction of fetal hormonal response and physiological parameters. In this book physiologists, pediatricians and obstetricians active in experimental studies in both physiology and endocrinology combine both aspects of investigations. Historical remarks on the endocrine development of the fetus are followed by observations of the hormonal control of the cardiovascular system. Basic mechanisms of fetal endocrine control such as brain development, fetal growth, fetal behaviour, and thermoregulation are given particular consideration. Finally, carbohydrate metabolism and the mechanism of parturition are outlined.

It is a truism that as we age there are a number of underlying physiological changes conspiring to alter our level of behavioral and cognitive function ing. Despite the inherent interrelatedness of these behavioral and cognitive changes, all too often the papers we read confine themselves to specific, isolated components of the developing process. Although exceptions nat urally exist, we believe that these exceptions should become rule. Although an integrated approach is important in all areas of adult devel opment, it is perhaps particularly germane in the study of atypical aging. Here, changes in overall functioning can occur in rapid succession, with the synchrony of decline between different subprocesses making it difficult to factor changes in one process from changes in another. For example, because changes in cognitive functioning co-occur with other dramatic changes in (motoric) response capacities, it is unclear how one can effec tively study changes in the ability to cognize independent of changes in the very mechanisms (ability to execute motor sequences) so often used to index cognitive performance."

It has been my privilege and pleasure during the past half century to participate in the unfolding of present-day concepts of the mammalian female reproductive cycles. When the studies recorded here began in the late 1930s it was already established that cyclic ovarian function is governed by gonadotropic secretions from the anterior pituitary gland, the "conductor of the endrocrine orchestra," and that in turn this activity is importantly dependent in some way upon secretion of estro gens and progesterone by the ovaries. Although a role of the nervous system was recognized for the reflex-like induction of ovulation in rabbits and cats and the in duction of pseudopregnancy in rats and mice, and although there was even some evidence of neural participation in ovulation in rats, a major central neural role in the female cycle of most species was not apparent. Gonadotropic fractions of pitui tary extracts having distinct follicle-stimulating and luteinizing activities in test ani mals had been obtained, and these respective effects had been fairly well charac terized. Prolactin was well known for its lactogenic activity, but its luteotropic role in rats and mice had yet to be revealed. The molecular structure of the several estro gens and progesterone was known, and they were readily available as synthetic pro ducts. The broad concept of ovarian-pituitary reciprocity appeared to be an accept able explanation of the female cycle, with the ovary in control through the rhythmic rise and fall in secretion of follicular estrogen.

Research in diabetes has accelerated in two areas, both of which are being reviewed in CTMI. The first is the use of a variety of animal models; the second is basic research in human investigation, islet cell antigens, and mapping of genes as sociated with susceptibility to disease. Dr. Thomas Dyrberg accepted editorial responsibility for this volume, which covers the first area. A second book, to be published later in the year, is edited by Drs. Brekkeskov and Hansen (CTMI 164, see page VI for contents). Although the contributors to both volumes represent the international scientific community, the editors are from the Hagedorn Research Laboratory in Denmark. Work at this institute and the Steno Memorial Hospital has been dedicated to research in diabetes for decades, and the insti tutions were appointed WHO Collaborating Centres for Re search and Training on the Pathogenesis of Diabetes Mellitus in 1983. It is worth noting that while addressing the hypothesis of the role of class II major histocompatibility glycoproteins in autoimmune diabetes (insulin-dependent diabetes, IDDM) a number of investigators established animal models in which class II molecules were expressed under the control of the rat insulin promoter. While generating interesting information on 100M, the finding of immunologic tolerance in such transgenic mice has attracted the attention of several basic immunologic laboratories for quite different reasons. Thus, we are reminded again of the Pasteur dictum that "chance favors the prepared mind. " Michael B. A. Oldstone, M. D."

The account of "neonatal sterilization" is the story of the advocates of direct effect of steroids on the gonads and those who believed in the indirect influence, mediated through the hypothalamus and/or the pituitary gland. As often happens in biology, both convictions represent the same image seen from different perspectives. Prof DC Johnson (Kansas City, KS) reminisced the beginning of the story in a letter to me. I am paraphrasing parts of the letter with his permission. "As a starting point we could pick the life-long research of Emil Steinach ... " Steinach recognized the influence of testes on the develop ment of accessory sex organs in 1894, described virilization of females and feminization of males in 1913, and identified the controlling influence of the hypophysis on the gonads in 1928. He reviewed his work in a book Sex and Life, Forty Years of Biological and Medical Experience (E Steinach and L Loebe!; Faber and Faber, London, 1940). He got on the wrong road in later years and that is the reason everybody seems to have forgotten him. He presented his hypothesis that estrogen has a direct effect upon the testes, i. e. hormone antagonism, at the 1st International Congress on Sex Research in 1926.

This monograph represents the first comprehensive review of hormones in human amniotic fluid and includes data published up to and including 1980. Recently, more extensive use of amniocentesis for prenatal diagnosis and evaluation of fetal lung maturation has shown that amniotic fluid hormone measurements can aid in the diagnosis of fetal and placental abnormalities. The material is presented in two main sections dealing with steroid and protein hormones. The methods of identification and quantitation are delineated, and the findings are discussed in relation to the clinical conditions. In addition, particular attention has been directed towards up-to-date review of the sources, metabolism and transfer of human amniotic fluid hormones. The review is intended to serve the needs of clinicians, basic scientists and students, providing detailed information on human amniotic fluid hormones in order to improve patient care and indicate possibilities for further investigations. Ttibingen, January 1982 A.E. Schindler Contents Introduction A. 1 Origin of Human Amniotic Fluid . 2 B. C. Origin and Regulation of Steroids in Human Amniotic Fluid . 5 D. Methods of Isolation and Identification of Steroids in Human Amniotic Fluid 6 I. C , C , and C Steroids . 6 30 29 28 II. C Steroids 6 27 1. Cholesterol 6 2. Cholestanol . 6 3. ,::l7 -Cholestenol and ,::l8 -Cholestenol. 6 4. 7-Dehydrocholesterol and Desmosterol . 6 ,::l5_C Steroids. III. 7 21 1. Pregnenolone 7 2. 16cx-H ydroxypregnenolone. 7 3. 17cx-Hydroxypregnenolone.

Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems."

Dr. Raymond Pederson, Dr. Jill Dryburgh and I commenced work on GIP in 1968, when, with the generous help of Professor Viktor Mutt and Professor Erik Jorpes of the Karolinska Inst, itute, Stockholm, we were able to establish that there existed an inhibitory material for acid secretion in cholecystokinin-pancreozymin prepara tions. Once the physiological evidence for the inhibitor was established it seemed appropriate to seek help in its isolation. Dr. J. Dryburgh and Dr. R. Pederson were left to bioassay fractions in Vancouver whilst I enjoyed the company of Professor Mutt at the Karolinska for one year, as a Medical Research Council of Canada Visiting Scientist. Purification of the inhibitory factor proceeded rapidly due, in no small measure, to Professor Mutt's untirmg efforts on my behalf. Later that year, Dr. Dryburgh joined us in Stockholm to begin the sequence work on GIP. This was completed late in 1970 in Vancouver. In Stockholm in June 1970, I met a fellow Canadian Dr. John Dupre (McGill University) at a cocktail party who kept commenting about the possibility of GIP being an insulinotropic hormone, the "incretin" of earlier days. At that time, gastrointestinal physiologist as I was, I did not recognize the importance of his comment. This became apparent two or three years later when Dr. Dupre demonstrated that GIP was insulinotropic in man. In 1972, Maryanne Kuzio and Dr."

Contraceptives have always provided ground for controversy. This book describes and discusses latest findings concerning the advantages as well as hazard and risk factors of contraception. The clinical impact of oral contraceptives on metabolism is particularly highlighted. In addition, behavioral methods, intrauterine devices, implants and modern approaches in animal and clinical research in the field of immunization against pregnancy are considered. Last, but not least, the book summarizes the complex ethical, religious and political aspects of family planning and contraception.

It is about 15 years since the first presentation on uteroglobin was given to a group of developmental biologists, reproductive physiologists, and geneticists who had gathered in November 1966 at Konstanz (Germany). In the following decade so much knowledge was accumulated that a special symposium seemed appropriate. This was organized as a satellite symposium to the International Congress of Endocrinology at Hamburg and brought together 50 scientists at Aachen. These scientists, working in the field of pro teins and steroids, in early pregnancy, recognized the impact of what had been reported, and many of them later agreed to contribute to this booN. and thus to present their research d, ta available until December 1980. The present volume covers a relatively broad spectrum of data and observations which shed some light on preimplantational embryonic life and on the supports and obstacles provided by the maternal organism with respect to final accomplishment of normal im plantation and establishment of pregnancy. The book will serve both as a textbook and as a scientific dictionary for Ph.D. students, postdoctoral fellows and advanced scientists working in this area. The course of early pregnancy depends very much on a proper balance of steroid hor mones, and the induction of protein synthesis by steroid hormones is one of the well known fundamental processes in cellular differentiation and embryonic development."

The epididymis has great significance in the reproductive biology of the male and it is gaining recognition as an organ worthy of study in its own right - where the secretory and absorptive activities of one tissue (the epithelium) profoundly modify the function of another (the spermatozoon). Apart from cases of epididymal agenesis or physical blockage, however, it is not yet known to what extent mal functions of the epididymis contribute to "unexplained" male infer tility, but its importance as a target for antifertility agents in the male is now widely appreciated. This monograph evolved from two lectures on epididymal func tion given at the National Research Institute for Family Planning, Beijing and the Sichuan Provincial Family Planning Research Insti tute, Chengdu, China in 1983. In order to stress for this audience the central importance of the epididymis in fertilisation, and so highlight its potential for attack by antifertility agents, the talks attempted to put the epididymis in reproductive perspective by stressing the func tional development of the sperm cells during their sojourn in the epididymis, rather than merely listing the changes observed in them."

Sixteen years is a long time, not only in human life but also in the rapid history of contemporary endocrinology. Since the publication of the first edition of this monograph, numerous new lines of research and discoveries have greatly contrib- uted to our knowledge of the physiological and pathological regulation of aldos- terone biosynthesis in man and animals. The first reports about a sensitive ra- dioimmunoassay for plasma aldosterone and about a preparation of dispersed zona glomerulosa cells were published in 1970 (Mayes et al. 1970; Haning et al. 1970). These two developments alone turned out to have a tremendous impact on research in aldosterone physiology (for reviews see Coghlan et al. 1979b; J. F. Tait et al. 1980b). In 1971, atrial natriuretic peptides, somatostatin, and the precursor molecule of ACTH had not yet been discovered. Angiotensin antagonists and con- verting-enzyme inhibitors were not yet available. The clinical syndrome of hypo- reninemic hypo aldosteronism was unknown. The possible roles of prostaglandins and dopamine in the control of aldosterone pwduction had not been considered. Cyclic AMP was then the only substance with a clearly established second-mes- senger function.

A cutting-edge review of how derangements in the hormonal and growth factor mechanisms controlling normal mammary development lead to breast cancer. Drawing on the multidisciplinary expertise of leading authorities, the book highlights the roles of oncogenes and tumor suppressor genes, spelling out the importance of autocrine/paracrine loops (e.g., stromal epithelial interactions) in supporting breast cancer cell proliferation and the progression to hormone independence. The book's many prominent contributors also illuminate significant recent advances in the biochemistry and physiology of hormone receptors and review the state-of -the-art in the endocrine therapy of breast cancer. Endocrinology of Breast Cancer provides a unique integrated overview of the most significant basic and clinical developments concerning the hormonal aspects of breast cancer.

Since the first description of Philadelphia chromosome-negative chronic myeloproliferative disorders more than 100 years ago, the diagnosis and therapy of these conditions have been based primarily on clinical experience and judgement. Until recently very little was known about the molecular basis of these diseases. In order to spark research in this area basic scientists and clinicians from various parts of the world have contributed to this volume, the first of its kind to put together the current knowledge. The book deals with the new WHO classification of these disorders, novel aspects of diagnostic pathology, the search for disease-relevant genes utilizing molecular biology and proteomic techniques, the description of the roles of PVR-1 and VHL genes for polycythemias and the discovery of the gene mutation responsible for the idiopathic hypereosinophilic syndrome. A chapter on anagrelide, an important novel drug for the treatment of primary thrombocythemia, is included.

Describes the ability of a series of endocrine-derived compounds, i.e. CHRH, LHRH, somatostatin, anti-androgens, and aromatase inhibitors to exert a direct anti-neoplastic activity or to potentiate the activity of traditional chemotherapeutic agents on neuroendocrine and solid tumors. In addition, a new class of potent GH-releasers, GSHs/Ghrelin, endowed with important endocrine and extra-endcocrine action, is presented. Therefore, in addition to traditional chemotherapy, characterized by high toxicity and non-selective action on tumoral cells, the reader can find a new approach with more selective, less cytotoxic endocrine derived compounds.

In 2001 we wrote the book Graves' Disease: A Practical Guide (McFarland), which described the causes, diagnosis, treatment and disease course of Graves' disease and other hyperthyroid disorders, such as toxic multinodular goiter, thyroiditis, resistance to thyroid hormone, and hyperthyroidism caused by medications and genetic mutations. The present work continues the above but focuses on subsequent advances in disease pathology, including discoveries regarding the genetic, immune system, and environmental factors that lead to hyperthyroid disorders; new guidelines for conventional treatment; and alternative and complementary medical therapies are included. Additional sections describe special circumstances such as hyperthyroidism in pregnancy and in children, and transient hyperthyroidism in the newborn.

The Fifteenth Midwest Conference on Endocrinology and Metabolism, held at the University of Missouri-Columbia on October 11 and 12th, 1979, hosted the most prominent active researchers in the world on the subject of the hormone relaxin. Each speaker presented an in-depth coverage of his chosen topic and area of expertise. Some of the data presented in this book are findings which have not been pub lished in a scientific journal. The topic of this conference is especially timely in light of the fact that this is a first confer ence devoted specifically to the hormone relaxin. Progress on this hormone has been exceedingly rapid in recent years and many signif icant breakthroughs are documented in these pages. Lively discus sions following each presentation attest to the enthusiastic research effort being pursued at the present time concerning relaxin. Traditionally the Midwest Conferences on Endocrinology and Metabolism have emphasized breadth as well as depth of coverage. The present Conference has covered the many active areas of research in relaxin, including morphological aspects of the hormone's origin, chemical purification and chemical structure, bioassays, radioimmuno assays, receptors, mechanism of biochemical action and physiological responses to the hormone. Advances in relaxin were slow since its discovery by Dr. Frederick Hisaw, Sr. in 1926 until the availability of homogenous preparations some seven years ago. In the suceeding seven years, activity in the subject has accelerated remarkably."

This book was written at the invitation of Dr. H. GOTZE of Springer-Verlag for the series "Monographs in Endocrinology." It is not a comprehensive account of the prostaglandins but has been writ ten with a deliberate emphasis upon those aspects of the field in which I am particularly interested and to which, in some cases, I have made a contribution. I am grateful to Miss E. PFISTERER and her colleagues of Springer Verlag for their excellent work. I should also like to thank my wife without whose patience, encouragement and help this book would never have been completed. Finally this is an appropriate time to express my sincere gratitude to those scientists who over the years have given me samples of prostaglandins-namely Professors S.BERGSTROM and B.SAMUELSSON of the Karolinska Institute, Stockholm, Professor D. A. VAN DORP of the Unilever Research Laboratories, Vlaardingen and Dr. J. E. PIlm of the Upjohn Company, Kalamazoo. Without their help work in this field would have been extremely difficult."